Neonatal acute kidney disease in the NCCHD-neoAKI Cohort: risk factors and prognostic outcomes

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Although widely recognized in adults and children, its significance in neonates is unclear. We aimed to investigate the risk factors and outcomes of neonatal AKD in a cohort of neonates with acute kidney injury (AKI). Methods: We performed a retrospective cohort study at a tertiary NICU in Japan. Among 345 neonates with AKI between 2014 and 2024, 280 were included after excluding cases with congenital kidney disease, early death (< 7 days), or missing data. AKD was defined by KDIGO/ADQI criteria. We compared clinical features and outcomes between neonates with and without AKD and used multivariable logistic regression to identify predictors. Results: Of 280 neonates with AKI, 85 (30%) developed AKD. Compared to non-AKD neonates, those with AKD had higher 90-day mortality (8% vs. 2%, P = 0.005) and MAKE90 (17% vs. 7%, P = 0.014). Chronic lung disease (78% vs. 50%, P < 0.001) and intraventricular hemorrhage (38% vs 16%, P = 0.002) were also more common in the AKD group. In multivariable analysis, aminoglycoside exposure (OR = 2.04; 95% CI, 1.07–4.04; P = 0.031) and lower birth weight (per 100 g) (OR = 2.73; 95% CI, 1.11–1.22; P = 0.002) were independently associated with AKD. Conclusion: Neonatal AKD was common and associated with increased mortality and major adverse kidney events. Our findings support AKD as a useful concept for identifying high-risk neonates and highlight the need for long-term kidney monitoring in this vulnerable population. neonate acute kidney injury NICU children nephrotoxic medications chronic kidney disease Figures Figure 1 Introduction Acute kidney disease (AKD) is defined as acute or subacute kidney dysfunction or damage persisting for 7 to 90 days after an initiating event [ 1 , 2 ]. This concept has received increasing attention in adult and pediatric populations due to its association with adverse outcomes, including progression to chronic kidney disease (CKD) and increased mortality [ 2 – 9 ]. However, the clinical significance of AKD in neonates remains largely unexplored. Acute kidney injury (AKI) affects approximately 30% of critically ill neonates and is associated with a 10% mortality rate and a 13% risk of progression to CKD [ 10 – 12 ]. Despite its relevance, research on neonatal AKI remains notably limited. A PubMed search conducted on January 30, 2025, for "acute kidney injury" yielded approximately 79,300 articles, but only 237 (0.3%) specifically addressed neonates. Furthermore, studies focusing on neonatal AKD, which is a broader concept that includes AKI, are almost entirely absent from the literature. Neonates are at a higher risk of kidney dysfunction and long-term health issues because their kidneys are not fully developed, and their care in neonatal intensive care units (NICUs) is highly complex. AKD in neonates likely worsens these challenges, making them more prone to multi-organ dysfunction and long-term health complications. Moreover, limited collaboration between nephrologists and neonatologists hinders comprehensive research and clinical management in this critical area [ 12 ]. To address these gaps, we established the NCCHD-neoAKI cohort, a team-based project combining knowledge in neonatology, nephrology, and infectious diseases. This study aims to analyze data from the NCCHD-neoAKI cohort to (1) identify risk factors associated with neonatal AKD and (2) evaluate the outcomes of neonates with diagnosed AKD. We seek to advance understanding and contribute to the development of targeted strategies for the prevention and management of neonatal AKD. Methods Study design and participants This study was a single center retrospective study conducted at the National Center for Child Health and Development (NCCHD) in Japan. Data were obtained from the NCCHD-neoAKI cohort, a retrospective cohort established to investigate the epidemiology, risk factors, and outcomes of neonatal AKI and AKD. The NCCHD-neoAKI cohort includes 345 neonates admitted to the NICU at NCCHD between May 1, 2014 and May 31, 2024 who were within 28 days of age and met the criteria for AKI or AKD based on modified KDIGO or ADQI criteria [ 1 , 2 ]. For the present study, we applied additional exclusion criteria to define the study population. Neonates who died within 7 days of AKI onset were excluded because the definition of AKD requires kidney dysfunction persisting beyond 7 days. Neonates with congenital kidney disease were excluded as they represent a distinct population with different outcomes. Additionally, cases with incomplete clinical or laboratory data were excluded to maintain the validity and integrity of the analysis. Data collection The NCCHD-neoAKI cohort collects detailed clinical, demographic, and laboratory data on neonates with diagnosed AKI or AKD, including neonatal characteristics, perinatal complications, and treatment interventions. This dataset provides the basis for studying the epidemiology and outcomes of neonatal kidney disorders. For this study, we selected variables relevant to our research objectives from the cohort. The selected variables included demographic information (gestational age, birth weight, and sex), clinical data (mechanical ventilation, nephrotoxic drug exposure, surgery, and infection), and laboratory parameters (serum creatinine and urine output), ensuring alignment with the study’s aim to evaluate risk factors and outcomes of neonatal AKD. All data were collected retrospectively from electronic medical records and verified for accuracy. Outcomes The primary outcomes were mortality within 90 days, development of CKD stage ≥ 3, and major adverse kidney events at 90 days (MAKE90), as these outcomes directly reflect the clinical severity and long-term impact of neonatal AKD. The secondary outcomes included the presence of proteinuria, hypertension, chronic lung disease, and intraventricular hemorrhage, which were selected to provide additional insights into the complications and comorbidities associated with AKD. Outcomes were analyzed to compare differences between neonates with AKD and those without AKD. Additionally, potential risk factors for AKD were analyzed. Definitions AKI was defined according to the neonatal-modified KDIGO criteria [ 2 ] as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours, an increase to ≥ 1.5 times the baseline within 7 days, or a decrease in urine output to < 1 mL/kg/h for 24 hours or more. CKD stage ≥ 3 was defined as glomerular filtration rate (GFR) < 60 mL/min/1.73 m² persisting for at least 90 days [ 2 ]. AKD was defined as kidney dysfunction persisting between 7 and 90 days after an AKI event, incorporating both functional criteria, such as serum creatinine elevation, and markers of kidney damage, such as proteinuria. AKD was defined, according to KDIGO and ADQI guidelines, as acute or subacute kidney damage and/or loss of kidney function persisting for 7 to 90 days after an initiating event [ 1 , 2 ]. AKD can occur even when the criteria for AKI are not met, reflecting a broader spectrum of kidney dysfunction. MAKE90 were defined as a composite outcome of mortality, requirement for dialysis, or persistent kidney dysfunction 90 days after an exposure. Proteinuria was defined as a urine protein-to-creatinine ratio ≥ 0.5 mg/mg in infants under 2 years of age, ≥ 0.2 mg/mg in children aged 2 years or older, or a urine dipstick test showing ≥ 1 + protein [ 13 ]. Hypertension was defined as systolic or diastolic blood pressure exceeding the 95th percentile according to the Clinical Practice Guidelines of the American Academy of Pediatrics [ 14 ]. Intraventricular hemorrhage (IVH) was classified and graded based on cranial ultrasound findings according to the Papile classification system [ 15 ]. Chronic lung disease (CLD) was defined as oxygen dependency at 28 days of life or at 36 weeks’ postmenstrual age [ 16 ]. Nephrotoxic medications included aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAIDs), vancomycin, and other agents with known nephrotoxic effects [ 17 ]. The causes of kidney injury and underlying conditions were classified by four independent specialists, including a pediatric nephrologist, a neonatologist, and a pediatric infectious disease physician. Each physician selected the primary cause from predefined categories based on clinical judgment. In cases where opinions differed, the disagreement was resolved through review by an additional physician. Statistical analysis Continuous variables are expressed as the median and interquartile ranges (IQR) and categorical variables as the number (%). Normally distributed continuous variables were compared using the t -test, and non-normally distributed variables were compared using the Mann-Whitney U test. Categorical variables were compared using the χ 2 test. The risk factors for the development of AKD were evaluated by multivariate analyses using logistic regression. Variables included in the multivariate model were selected based on clinical relevance and statistical significance ( P < 0.1) in univariate analysis. The final model included birth weight, Apgar score at 5 minutes, aminoglycoside exposure, and AKI stage ≥ 2. Gestational age was not included in the final model due to its strong correlation with birth weight. All statistical analyses were performed with the JMP software package for Macintosh, 14.2 (SAS Institute Japan, Tokyo, Japan). Results were reported as odds ratios (OR) with 95% confidence intervals (CI). A two-tailed P value < 0.05 was considered statistically significant. Ethics This study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare, Japan. The study protocol was reviewed and approved by the Institutional Ethics Committee of the National Center for Child Health and Development (approval number: 2024 − 074). Given the retrospective and anonymized nature of the data, the need for informed consent was waived by the ethics committee. However, we ensured transparency by publicly disclosing the study information on the institutional website, allowing participants or their guardians to opt out if desired. Results Overall patient characteristics During the study period, 345 neonates enrolled in the NCCHD-neoAKI cohort. Of these, 7 neonates who died within 7 days of AKI onset, 47 neonates with congenital kidney disease, and 11 cases with incomplete clinical or laboratory data were excluded from the study. A total of 280 neonates were included in the final analysis, of whom 85 (30%) progressed to AKD and 195 (70%) did not (Fig. 1 ). Table I shows the characteristics of the study cohort. The median gestational age and birth weight was 29 weeks (IQR, 26–33 weeks) and 1160 g (IQR, 716–1978 g), respectively. Nephrotoxic medications were administered to 207 (74%) neonates prior to AKI onset, with aminoglycosides being the most commonly used agent (n = 183, 65%). Underlying diseases were present in 217 (78%), with cardiac disease (n = 101, 36%) being the most frequent condition. Nephrotoxic medication exposure was the most common identified cause of AKI, followed by cardiac disease. Outcomes The outcomes of neonates with and without AKD are summarized in Table II. Among the 85 neonates who developed AKD, 7 (8%) died within 90 days. CKD stage ≥ 3 developed in 9 patients (11%), and 2 patients (2%) required dialysis. MAKE90 occurred in 14 patients (17%). Proteinuria was observed in 21 of 36 assessed patients (56%), whereas no patients (0/77, 0%) developed hypertension at 90 days. Chronic lung disease occurred in 64 patients (78%) and intraventricular hemorrhage in 32 patients (38%). Compared to the non-AKD group, neonates with AKD had significantly higher rates of 90-day mortality ( P = 0.005) and MAKE90 ( P = 0.014). Chronic lung disease was more common in the AKD group ( P < 0.001), as was intraventricular hemorrhage ( P = 0.002). There were no significant differences between groups in the frequency of CKD stage ≥ 3, dialysis, hypertension, or proteinuria. Risk factors for AKD development Patient characteristics between the AKD and non-AKD groups are shown in Table I. Compared to the non-AKD group, neonates who developed AKD had significantly lower gestational age (median 25 weeks vs. 30 weeks, P < 0.001) and birth weight (median 767 g vs. 1282 g, P < 0.001). The AKD group also had significantly lower Apgar scores at both 1 minute (median 3 vs. 5, P = 0.001) and 5 minutes (median 6 vs. 7, P = 0.004). The use of mechanical ventilation (n = 79 [96%] vs. n = 152 [80%], P < 0.001) and inotrope (n = 59 [72%] vs. n = 106 [56%], P = 0.015) were more frequent in the AKD group. Nephrotoxic medication exposure (n = 73 [87%] vs. n = 134 [68%], P = 0.001), particularly use of aminoglycoside (n = 67 [80%] vs. n = 116 [59%], P = 0.001) was significantly higher in the AKD group. Regarding the cause of AKI, drug-induced AKI was more common in the AKD group (n = 40 [52%] vs. n = 61 [36%], P = 0.002). Higher AKI stages at onset (Stage ≥ 2) tended to be more frequent among neonates who developed AKD (25 [30%] vs. n = 38 [20%], P = 0.06). In multivariate logistic regression analysis, lower birth weight (per 100 g) (OR = 2.73; 95% CI, 1.11–1.22; P = 0.002) and exposure to aminoglycoside (OR = 2.04; 95% CI, 1.07–4.04; P = 0.031) were identified as independent risk factors for AKD development after adjusting for other variables, including low Apgar score at 5 minutes and AKI stage ≥ 2 (Table III). Discussion In this study, we analyzed 280 neonates with AKI from the NCCHD-neoAKI cohort. Among them, 30% developed AKD. Neonates who developed AKD had higher risks of death, MAKE90, and progression to CKD. Exposure to aminoglycosides and lower birth weight were identified as independent risk factors for AKD. To our knowledge, this is one of the few studies worldwide that describes the epidemiology, risk factors, and outcomes of neonatal AKD in detail. Our study shows the need to recognize AKD early and plan long-term care. In the present study, neonatal AKD was associated with an increased risk of mortality and MAKE90. This finding is consistent with previous studies in adults and children [ 1 – 4 , 6 ], which have shown that kidney injury is not only a short-term problem but also has important effects on survival and long-term kidney function. Notably, Chawla et al. [ 1 ] and the KDIGO guidelines [ 2 ] have identified AKD as an independent risk factor for both death and progression to CKD. Our neonatal cohort expands this concept to the neonatal group. However, there were important differences compared to adults and children. Among the MAKE90 outcomes, death contributed more than CKD progression. In neonates, life outcomes are often affected by non-renal factors, which are related to prematurity and organ immaturity [ 12 , 15 , 18 ]. In some cases, patients died before CKD progression could be assessed. In addition, the kidney injuries in our cohort were often caused by nephrotoxic drugs, which tend to be reversible [ 8 , 9 , 17 ], and neonatal kidneys may have a relatively high capacity for recovery [ 1 , 8 , 9 ]. Furthermore, standard methods for evaluating kidney function, such as eGFR and proteinuria, are difficult to apply in neonates, which may have led to underestimation of CKD [ 2 , 13 , 14 ]. These findings suggest that neonatal AKD has a different outcome pattern compared to older patients, with mortality having a greater impact than CKD progression. However, the long-term effects on kidney function and kidney development in survivors require further study. In our cohort, neonates who developed AKD had lower gestational age and birth weight, lower Apgar scores, and were more likely to receive mechanical ventilation and vasoactive medications. These factors reflect greater illness severity and organ immaturity, which have been linked to kidney dysfunction in previous pediatric studies [ 7 – 9 , 12 ]. Nephrotoxic medications, especially aminoglycosides, were used more frequently in the AKD group, consistent with earlier reports highlighting the vulnerability of preterm kidneys to drug-related injury [ 8 , 9 , 17 ]. The most common causes of AKI in the AKD group were drug toxicity and cardiac disease, whereas non-AKD patients often had transient causes such as asphyxia or surgical procedures. Although most AKD cases started as AKI stage 1, the AKD group had more cases of stage 2, suggesting that even moderate AKI severity may be associated with persistent kidney dysfunction, as seen in older children [ 8 , 9 ]. In our cohort, exposure to aminoglycosides and lower birth weight were identified as independent risk factors for AKD. Aminoglycosides are widely used in NICUs for the treatment of sepsis and other infections, but their association with kidney injury is well documented, particularly in preterm infants with immature renal function [ 8 , 9 , 17 ]. Lower birth weight likely reflects a combination of immaturity, vulnerability to hemodynamic instability, and limited renal reserve, which may increase susceptibility to sustained kidney damage. Previous studies in children and adults have also reported that drug-induced kidney injury can lead to prolonged or persistent dysfunction [ 1 , 2 , 8 , 9 ]. Our findings confirm that both immaturity and nephrotoxic exposure contribute to the development of AKD in neonates. This underscores the importance of strategies to avoid nephrotoxic medications in high-risk neonates and to closely monitor those with low birth weight, as emphasized in prior quality improvement efforts such as the Baby NINJA program [ 17 ]. CLD and IVH were common in neonates with AKD. These complications largely reflect the high proportion of extremely and very low birth weight infants in this cohort [ 12 , 15 , 18 ]. While CLD and IVH are likely related to prematurity and overall illness severity, emerging evidence suggests potential bidirectional interactions between kidney injury and other organ dysfunctions, particularly lung injury [ 18 ]. Experimental and clinical studies have described pathways through which AKI can contribute to lung injury and vice versa, including inflammation, endothelial dysfunction, and fluid overload [ 18 – 21 ]. Although the present study was not designed to establish causality between AKD and CLD or IVH, our findings underline the need for further research into how kidney dysfunction may interact with other organ systems in critically ill neonates. This study has several limitations. First, it was a single-center retrospective study, which may limit the generalizability of the findings. Second, some secondary outcomes, particularly proteinuria and blood pressure, had missing data, which may have led to underestimation of CKD and hypertension [ 2 , 13 , 14 ]. Notably, among the neonates who were tested, proteinuria was common, suggesting it is an important marker for kidney monitoring after AKD. The low testing rate likely reflects limited collaboration between neonatologists and pediatric nephrologists, highlighting the need for better multidisciplinary follow-up. Third, we defined nephrotoxic medication exposure based only on aminoglycosides, vancomycin, NSAIDs, acyclovir/valacyclovir, and renin-angiotensin system-inhibitor. While we could not assess all potential nephrotoxic agents, these five drug classes are widely recognized as the most common nephrotoxic medications in neonatal AKI studies and likely captured the majority of relevant exposures. Finally, current AKI definitions in neonates, particularly extremely low birth weight infants, may capture non-pathological creatinine changes, risking overdiagnosis. In contrast, AKD criteria may better identify neonates with clinically significant and persistent kidney dysfunction. Our findings support AKD as a useful framework for recognizing neonates at higher risk of adverse outcomes. In conclusion, neonatal AKD was common and was associated with increased risks of mortality and major adverse kidney events. Exposure to aminoglycosides and lower birth weight were identified as independent risk factors. Our findings suggest that AKD is a valuable concept for identifying neonates at higher risk of poor outcomes. Improved collaboration between neonatologists and pediatric nephrologists is essential to monitor and manage long-term kidney health in this vulnerable population. Declarations Competing Interests: The authors have no conflicts of interest relevant to this article to disclose. An honorarium, grant, or other form of payment was not provided to any of the authors to produce the manuscript. Ethics Approval: This retrospective study was performed in line with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Health, Labour and Welfare, Japan. The protocol for the study received approval from the Ethics Committee of the NCCHD (Approval No.: 2024-074). Informed consent was deemed unnecessary according to these ethical guidelines. However, we ensured transparency by publicly disclosing the study information on the institutional website, allowing participants or their guardians to opt out if desired. Authors’ contributions KN prepared the first draft of the manuscript and was responsible for data collection supervision, data curation, formal analysis, investigation, and visualization. He also served as the primary investigator and supervised the project, including its administration. SO, TI, YM, and HA contributed to data collection and interpretation and participated in manuscript editing and review. HC performed data curation, formal analysis, investigation, and visualization. KF and TM revised the manuscript for important intellectual content. KK, TF, TI, and YI provided study supervision, critical manuscript revision, and contributed to funding acquisition. All authors were involved in the study’s conceptualization and design, approved the final manuscript, and agree to be accountable for all aspects of the work. Funding: This research was funded by a grant from the National Center for Child Health and Development (grant number: 2024B-9). Acknowledgments: The authors used ChatGPT (OpenAI) to assist with English editing of the manuscript draft. All edits were reviewed and finalized by the authors. Final language polishing was conducted by a professional editing service. We would like to thank the medical editor from the Center for Postgraduate Education and Training, National Center for Child Health and Development for editing a draft of this manuscript. Data availability: Deidentified individual participant’s data will not be made available. References Chawla LS, Bellomo R, Bihorac A, Acute Disease Quality Initiative Workgroup 16 et al (2017) Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol 13:241–257. https://doi.org/10.1038/nrneph.2017.2 Lameire NH, Levin A, Kellum JA et al (2021) Conference Participants. 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Overall patient characteristics and baseline comparison between the AKD and non-AKD groups All patients (n = 280) AKD group (n = 85) Non-AKD group (n = 195) P value Male 151 (54) 51 (61) 100 (51) 0.15 Gestational age (weeks) 29 (26–33) 25 (24–29) 30 (27–35) < 0.001 < 28 weeks 28–33 weeks ≥ 34 weeks 109 (39) 106 (37) 68 (24) 55 (65) 20 (24) 9 (11) 53 (27) 86 (44) 57 (29) < 0.001 Birth weight (g) 1160 (716–1978) 767 (554–1281) 1282 (854–2117) < 0.001 < 1000 g 1000–1500 g ≥ 1500 g 105 (37) 61 (22) 117 (41) 34 (40) 20 (24) 30 (36) 70 (36) 40 (20) 86 (44) 0.44 Apgar score at 1 min 4 (2–7) 3 (1–5) 5 (3–7) 0.001 Apgar score at 5 min 7 (5–8) 6 (5–8) 7 (5–8) 0.004 Age at AKI onset (days) 2 (2–4) 2 (2–4) 2 (2–5) 0.35 Ventilator * 231 (85) 79 (96) 152 (80) < 0.001 Inotrope * 165 (61) 59 (72) 106 (56) 0.015 Infection * 10 (4) 2 (2) 8 (4) 0.73 Sepsis * 9 (3) 4 (5) 5 (3) 0.46 Cardiac surgery * 2 (1) 1 (1) 1 (1) 0.51 Non-cardiac surgery* 15 (5) 3 (4) 12 (6) 0.56 Contrast agent * 4 (1) 1 (1) 3 (2) 1.00 Cardiac arrest * 1 (0.4) 0 (0) 1 (1) 1.00 Diuretics * 54 (19) 17 (20) 37 (19) 0.87 Nephrotoxic medications * 207 (74) 73 (87) 134 (68) 0.001 Aminoglycosides Vancomycin NSAIDs Acyclovir/valacyclovir RAS-inhibitor 183 (65) 5 (2) 83 (30) 0 (0) 0 (0) 67 (80) 0 (0) 29 (35) 0 (0) 0 (0) 116 (59) 5 (3) 54 (28) 0 (0) 0 (0) 0.001 0.33 0.26 NA NA Underlying disease 217 (78) 68 (81) 149 (76) 0.44 Cardiac Respiratory Kidney Others 101 (36) 12 (4) 6 (2) 100 (35) 36 (42) 1 (1) 1 (1) 31 (36) 65 (33) 10 (5) 5 (3) 70 (36) 0.26 Cause of AKI Drug-induced Cardiac disease Neonatal asphyxia Surgical procedures Prerenal causes Others 101 (36) 57 (20) 24 (8) 13 (5) 5 (2) 83 (29) 40 (52) 20 (26) 5 (6) 0 (0) 4 (5) 17 (20) 61 (36) 37 (22) 19 (11) 13 (8) 1 (1) 66 (34) 0.002 Stage at AKI onset Stage 1 Stage 2 Stage 3 213 (77) 63 (23) 0 (0) 58 (70) 25 (30) 0 (0) 155 (80) 38 (20) 0 (0) 0.06 Data are expressed as n (%) or median (interquartile range). AKI, acute kidney injury; AKD, acute kidney disease; NSAIDs, nonsteroidal anti-inflammatory drugs; RAS, renin-angiotensin system * Data collected before AKI onset. Table II. Outcomes of neonates with and without AKD All patients (n = 280) AKD group (n = 85) Non-AKD group (n = 195) P value Death within 90 days 10 (4) 7 (8) 3 (2) 0.005 CKD stage ≥ 3 19 (7) 9 (11) 10 (5) 0.12 Dialysis 2 (1) 2 (2) 0 (0) 0.09 MAKE90 27 (10) 14 (17) 13 (7) 0.014 Proteinuria * 47/102 (46) 20/36 (56) 27/66 (41) 0.21 Hypertension † 1/252 (0.4) 0/77 (0) 1/175 (1) 1.00 CLD 158 (59) 64 (78) 94 (50) < 0.001 IVH Grade 3–4 Grade 1–2 64 (23) 18 (6) 46 (16) 32 (38) 8 (10) 24 (29) 32 (16) 10 (5) 22 (11) 0.002 0.19 0.001 AKD , acute kidney disease; CKD , chronic kidney disease; CLD , chronic lung disease; IVH , intraventricular hemorrhage; MAKE90 , major adverse kidney events at 90 days * Proteinuria was assessed in 102 patients who underwent urine testing. † Hypertension was assessed in 252 patients with available blood pressure measurements. Table III. Multivariable logistic regression analysis of AKD development Factors Multivariate analysis OR 95% CI P value Lower birth weight per 100 g 2.73 1.11–1.22 0.002 Apgar score at 5 min 0.91 0.81–1.03 0.15 Exposure to aminoglycosides 2.04 1.07–4.04 0.031 AKI ≥ Stage 2 1.41 0.74–2.66 0.29 AKI, acute kidney injury; CI, confidence interval; OR, odds ratio Supplementary Files graphicabstractpediatricnephrology.pptx STROBEchecklistv4combinedPlosMedicine.docx Cite Share Download PDF Status: Published Journal Publication published 22 Oct, 2025 Read the published version in Pediatric Nephrology → Version 1 posted Reviewers agreed at journal 12 Jul, 2025 Reviewers invited by journal 10 Jul, 2025 Editor assigned by journal 04 Jul, 2025 First submitted to journal 03 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7037915","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":483420706,"identity":"cf1e36c7-824b-449f-801c-7a37375d7ff7","order_by":0,"name":"Kentaro Nishi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIie3QMQrCMBiG4U+EZAm4pgj1ChGhxdukCOlS9w4qgmuP0EN0E7dCwS5VV8dOmXoAJzGK4CBYu4nknULIQ/4EsNl+sT4IJKRrlgTssZV/RyYdyP0kIIP1i7TkU6rrGirc0kLXDZYueofP10w3zBcS0XyXKH+cojQTHuVHIgpGeHCN59mZkSHD3kxYiRZCNZeIQ9GBwDMkkk+y+IawO1HjrFKek4p8Qlrfciq1c8FsJMpC8yZeuQPe8mPvcxJedRHAChgk3YjNZrP9fTdACEAkc0kZ6QAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-3436-0392","institution":"National Center for Child Health and Development","correspondingAuthor":true,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Nishi","suffix":""},{"id":483420707,"identity":"616308a1-6756-4b02-b99e-f69f7ee1abaa","order_by":1,"name":"Kana Fukui","email":"","orcid":"","institution":"National Center for Child Health and 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Development","correspondingAuthor":false,"prefix":"","firstName":"Tatsuki","middleName":"","lastName":"Ikuse","suffix":""},{"id":483420711,"identity":"e88921d3-99d1-4dfc-b6bd-b44c2e9822eb","order_by":5,"name":"Yurina Miyata","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Yurina","middleName":"","lastName":"Miyata","suffix":""},{"id":483420712,"identity":"f6b978b9-b1a0-4a52-93e2-bf0cf3dd0bc9","order_by":6,"name":"Hiroyuki Aiba","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Aiba","suffix":""},{"id":483420713,"identity":"7a552680-c288-4f73-ac75-d2cd56afeda2","order_by":7,"name":"Hirotaka Chiba","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Hirotaka","middleName":"","lastName":"Chiba","suffix":""},{"id":483420714,"identity":"20728529-0bce-41f1-bce8-25d81a1fb26b","order_by":8,"name":"Takanori Funaki","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Takanori","middleName":"","lastName":"Funaki","suffix":""},{"id":483420715,"identity":"aefa563a-f82d-4f0c-b24d-b65eb027c93c","order_by":9,"name":"Tetsuya Isayama","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Tetsuya","middleName":"","lastName":"Isayama","suffix":""},{"id":483420716,"identity":"fea278a8-ad8c-4410-b868-f9df1f4cb9c7","order_by":10,"name":"Yushi Ito","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Yushi","middleName":"","lastName":"Ito","suffix":""},{"id":483420717,"identity":"5c0125df-4d32-49b9-9cf3-7235eb3335e9","order_by":11,"name":"Koichi Kamei","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Kamei","suffix":""}],"badges":[],"createdAt":"2025-07-03 11:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7037915/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7037915/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-025-07011-w","type":"published","date":"2025-10-22T16:16:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86674039,"identity":"4668acc1-be9f-4d69-b84f-614e8d350fdc","added_by":"auto","created_at":"2025-07-14 11:51:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17069,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patient selection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAKD\u003c/strong\u003e, acute kidney disease; \u003cstrong\u003eAKI\u003c/strong\u003e, acute kidney injury; NCCHD, National Center for Child Health and Development\u003c/p\u003e","description":"","filename":"Fig.png","url":"https://assets-eu.researchsquare.com/files/rs-7037915/v1/99913ff29b543d742ce6e982.png"},{"id":94490162,"identity":"678d2df2-0fcf-4ed4-ad5d-8bb45d7f5f58","added_by":"auto","created_at":"2025-10-27 17:07:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":795410,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7037915/v1/56b5faab-d2a4-4cd7-95a7-bb5f4c251621.pdf"},{"id":86675479,"identity":"9dae121a-9d4c-4e05-ba7f-405153a4ffa9","added_by":"auto","created_at":"2025-07-14 11:59:41","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":287907,"visible":true,"origin":"","legend":"","description":"","filename":"graphicabstractpediatricnephrology.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7037915/v1/aee90d8f81e6fb4b999900b6.pptx"},{"id":86674042,"identity":"0c5d1711-53ad-49cc-bc1d-685ab4a94a29","added_by":"auto","created_at":"2025-07-14 11:51:41","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36610,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistv4combinedPlosMedicine.docx","url":"https://assets-eu.researchsquare.com/files/rs-7037915/v1/7f5a3c56cb62869d4e8ec4b5.docx"}],"financialInterests":"","formattedTitle":"Neonatal acute kidney disease in the NCCHD-neoAKI Cohort: risk factors and prognostic outcomes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute kidney disease (AKD) is defined as acute or subacute kidney dysfunction or damage persisting for 7 to 90 days after an initiating event [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This concept has received increasing attention in adult and pediatric populations due to its association with adverse outcomes, including progression to chronic kidney disease (CKD) and increased mortality [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the clinical significance of AKD in neonates remains largely unexplored.\u003c/p\u003e\u003cp\u003eAcute kidney injury (AKI) affects approximately 30% of critically ill neonates and is associated with a 10% mortality rate and a 13% risk of progression to CKD [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR11\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite its relevance, research on neonatal AKI remains notably limited. A PubMed search conducted on January 30, 2025, for \"acute kidney injury\" yielded approximately 79,300 articles, but only 237 (0.3%) specifically addressed neonates. Furthermore, studies focusing on neonatal AKD, which is a broader concept that includes AKI, are almost entirely absent from the literature. Neonates are at a higher risk of kidney dysfunction and long-term health issues because their kidneys are not fully developed, and their care in neonatal intensive care units (NICUs) is highly complex. AKD in neonates likely worsens these challenges, making them more prone to multi-organ dysfunction and long-term health complications. Moreover, limited collaboration between nephrologists and neonatologists hinders comprehensive research and clinical management in this critical area [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo address these gaps, we established the NCCHD-neoAKI cohort, a team-based project combining knowledge in neonatology, nephrology, and infectious diseases. This study aims to analyze data from the NCCHD-neoAKI cohort to (1) identify risk factors associated with neonatal AKD and (2) evaluate the outcomes of neonates with diagnosed AKD. We seek to advance understanding and contribute to the development of targeted strategies for the prevention and management of neonatal AKD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and participants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study was a single center retrospective study conducted at the National Center for Child Health and Development (NCCHD) in Japan. Data were obtained from the NCCHD-neoAKI cohort, a retrospective cohort established to investigate the epidemiology, risk factors, and outcomes of neonatal AKI and AKD. The NCCHD-neoAKI cohort includes 345 neonates admitted to the NICU at NCCHD between May 1, 2014 and May 31, 2024 who were within 28 days of age and met the criteria for AKI or AKD based on modified KDIGO or ADQI criteria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For the present study, we applied additional exclusion criteria to define the study population. Neonates who died within 7 days of AKI onset were excluded because the definition of AKD requires kidney dysfunction persisting beyond 7 days. Neonates with congenital kidney disease were excluded as they represent a distinct population with different outcomes. Additionally, cases with incomplete clinical or laboratory data were excluded to maintain the validity and integrity of the analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData collection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe NCCHD-neoAKI cohort collects detailed clinical, demographic, and laboratory data on neonates with diagnosed AKI or AKD, including neonatal characteristics, perinatal complications, and treatment interventions. This dataset provides the basis for studying the epidemiology and outcomes of neonatal kidney disorders. For this study, we selected variables relevant to our research objectives from the cohort. The selected variables included demographic information (gestational age, birth weight, and sex), clinical data (mechanical ventilation, nephrotoxic drug exposure, surgery, and infection), and laboratory parameters (serum creatinine and urine output), ensuring alignment with the study\u0026rsquo;s aim to evaluate risk factors and outcomes of neonatal AKD. All data were collected retrospectively from electronic medical records and verified for accuracy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary outcomes were mortality within 90 days, development of CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3, and major adverse kidney events at 90 days (MAKE90), as these outcomes directly reflect the clinical severity and long-term impact of neonatal AKD. The secondary outcomes included the presence of proteinuria, hypertension, chronic lung disease, and intraventricular hemorrhage, which were selected to provide additional insights into the complications and comorbidities associated with AKD. Outcomes were analyzed to compare differences between neonates with AKD and those without AKD. Additionally, potential risk factors for AKD were analyzed.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDefinitions\u003c/strong\u003e\u003cp\u003eAKI was defined according to the neonatal-modified KDIGO criteria [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] as an increase in serum creatinine by \u0026ge;\u0026thinsp;0.3 mg/dL within 48 hours, an increase to \u0026ge;\u0026thinsp;1.5 times the baseline within 7 days, or a decrease in urine output to \u0026lt;\u0026thinsp;1 mL/kg/h for 24 hours or more. CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3 was defined as glomerular filtration rate (GFR)\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73 m\u0026sup2; persisting for at least 90 days [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. AKD was defined as kidney dysfunction persisting between 7 and 90 days after an AKI event, incorporating both functional criteria, such as serum creatinine elevation, and markers of kidney damage, such as proteinuria. AKD was defined, according to KDIGO and ADQI guidelines, as acute or subacute kidney damage and/or loss of kidney function persisting for 7 to 90 days after an initiating event [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. AKD can occur even when the criteria for AKI are not met, reflecting a broader spectrum of kidney dysfunction. MAKE90 were defined as a composite outcome of mortality, requirement for dialysis, or persistent kidney dysfunction 90 days after an exposure. Proteinuria was defined as a urine protein-to-creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;0.5 mg/mg in infants under 2 years of age, \u0026ge; 0.2 mg/mg in children aged 2 years or older, or a urine dipstick test showing\u0026thinsp;\u0026ge;\u0026thinsp;1\u0026thinsp;+\u0026thinsp;protein [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Hypertension was defined as systolic or diastolic blood pressure exceeding the 95th percentile according to the Clinical Practice Guidelines of the American Academy of Pediatrics [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Intraventricular hemorrhage (IVH) was classified and graded based on cranial ultrasound findings according to the Papile classification system [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Chronic lung disease (CLD) was defined as oxygen dependency at 28 days of life or at 36 weeks\u0026rsquo; postmenstrual age [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nephrotoxic medications included aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAIDs), vancomycin, and other agents with known nephrotoxic effects [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The causes of kidney injury and underlying conditions were classified by four independent specialists, including a pediatric nephrologist, a neonatologist, and a pediatric infectious disease physician. Each physician selected the primary cause from predefined categories based on clinical judgment. In cases where opinions differed, the disagreement was resolved through review by an additional physician.\u003c/p\u003e\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables are expressed as the median and interquartile ranges (IQR) and categorical variables as the number (%). Normally distributed continuous variables were compared using the \u003cem\u003et\u003c/em\u003e-test, and non-normally distributed variables were compared using the Mann-Whitney \u003cem\u003eU\u003c/em\u003e test. Categorical variables were compared using the χ\u003csup\u003e2\u003c/sup\u003e test. The risk factors for the development of AKD were evaluated by multivariate analyses using logistic regression. Variables included in the multivariate model were selected based on clinical relevance and statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1) in univariate analysis. The final model included birth weight, Apgar score at 5 minutes, aminoglycoside exposure, and AKI stage\u0026thinsp;\u0026ge;\u0026thinsp;2. Gestational age was not included in the final model due to its strong correlation with birth weight. All statistical analyses were performed with the JMP software package for Macintosh, 14.2 (SAS Institute Japan, Tokyo, Japan). Results were reported as odds ratios (OR) with 95% confidence intervals (CI). A two-tailed \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthics\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare, Japan. The study protocol was reviewed and approved by the Institutional Ethics Committee of the National Center for Child Health and Development (approval number: 2024\u0026thinsp;\u0026minus;\u0026thinsp;074). Given the retrospective and anonymized nature of the data, the need for informed consent was waived by the ethics committee. However, we ensured transparency by publicly disclosing the study information on the institutional website, allowing participants or their guardians to opt out if desired.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eOverall patient characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDuring the study period, 345 neonates enrolled in the NCCHD-neoAKI cohort. Of these, 7 neonates who died within 7 days of AKI onset, 47 neonates with congenital kidney disease, and 11 cases with incomplete clinical or laboratory data were excluded from the study. A total of 280 neonates were included in the final analysis, of whom 85 (30%) progressed to AKD and 195 (70%) did not (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTable I shows the characteristics of the study cohort. The median gestational age and birth weight was 29 weeks (IQR, 26\u0026ndash;33 weeks) and 1160 g (IQR, 716\u0026ndash;1978 g), respectively. Nephrotoxic medications were administered to 207 (74%) neonates prior to AKI onset, with aminoglycosides being the most commonly used agent (n\u0026thinsp;=\u0026thinsp;183, 65%). Underlying diseases were present in 217 (78%), with cardiac disease (n\u0026thinsp;=\u0026thinsp;101, 36%) being the most frequent condition. Nephrotoxic medication exposure was the most common identified cause of AKI, followed by cardiac disease.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe outcomes of neonates with and without AKD are summarized in Table II. Among the 85 neonates who developed AKD, 7 (8%) died within 90 days. CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3 developed in 9 patients (11%), and 2 patients (2%) required dialysis. MAKE90 occurred in 14 patients (17%). Proteinuria was observed in 21 of 36 assessed patients (56%), whereas no patients (0/77, 0%) developed hypertension at 90 days. Chronic lung disease occurred in 64 patients (78%) and intraventricular hemorrhage in 32 patients (38%).\u003c/p\u003e\u003cp\u003eCompared to the non-AKD group, neonates with AKD had significantly higher rates of 90-day mortality (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) and MAKE90 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). Chronic lung disease was more common in the AKD group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as was intraventricular hemorrhage (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). There were no significant differences between groups in the frequency of CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3, dialysis, hypertension, or proteinuria.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk factors for AKD development\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePatient characteristics between the AKD and non-AKD groups are shown in Table I. Compared to the non-AKD group, neonates who developed AKD had significantly lower gestational age (median 25 weeks vs. 30 weeks, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and birth weight (median 767 g vs. 1282 g, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The AKD group also had significantly lower Apgar scores at both 1 minute (median 3 vs. 5, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and 5 minutes (median 6 vs. 7, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). The use of mechanical ventilation (n\u0026thinsp;=\u0026thinsp;79 [96%] vs. n\u0026thinsp;=\u0026thinsp;152 [80%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and inotrope (n\u0026thinsp;=\u0026thinsp;59 [72%] vs. n\u0026thinsp;=\u0026thinsp;106 [56%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) were more frequent in the AKD group. Nephrotoxic medication exposure (n\u0026thinsp;=\u0026thinsp;73 [87%] vs. n\u0026thinsp;=\u0026thinsp;134 [68%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), particularly use of aminoglycoside (n\u0026thinsp;=\u0026thinsp;67 [80%] vs. n\u0026thinsp;=\u0026thinsp;116 [59%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) was significantly higher in the AKD group. Regarding the cause of AKI, drug-induced AKI was more common in the AKD group (n\u0026thinsp;=\u0026thinsp;40 [52%] vs. n\u0026thinsp;=\u0026thinsp;61 [36%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). Higher AKI stages at onset (Stage\u0026thinsp;\u0026ge;\u0026thinsp;2) tended to be more frequent among neonates who developed AKD (25 [30%] vs. n\u0026thinsp;=\u0026thinsp;38 [20%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06).\u003c/p\u003e\u003cp\u003eIn multivariate logistic regression analysis, lower birth weight (per 100 g) (OR\u0026thinsp;=\u0026thinsp;2.73; 95% CI, 1.11\u0026ndash;1.22; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) and exposure to aminoglycoside (OR\u0026thinsp;=\u0026thinsp;2.04; 95% CI, 1.07\u0026ndash;4.04; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) were identified as independent risk factors for AKD development after adjusting for other variables, including low Apgar score at 5 minutes and AKI stage\u0026thinsp;\u0026ge;\u0026thinsp;2 (Table III).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we analyzed 280 neonates with AKI from the NCCHD-neoAKI cohort. Among them, 30% developed AKD. Neonates who developed AKD had higher risks of death, MAKE90, and progression to CKD. Exposure to aminoglycosides and lower birth weight were identified as independent risk factors for AKD. To our knowledge, this is one of the few studies worldwide that describes the epidemiology, risk factors, and outcomes of neonatal AKD in detail. Our study shows the need to recognize AKD early and plan long-term care.\u003c/p\u003e\u003cp\u003eIn the present study, neonatal AKD was associated with an increased risk of mortality and MAKE90. This finding is consistent with previous studies in adults and children [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e], which have shown that kidney injury is not only a short-term problem but also has important effects on survival and long-term kidney function. Notably, Chawla et al. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and the KDIGO guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] have identified AKD as an independent risk factor for both death and progression to CKD. Our neonatal cohort expands this concept to the neonatal group. However, there were important differences compared to adults and children. Among the MAKE90 outcomes, death contributed more than CKD progression. In neonates, life outcomes are often affected by non-renal factors, which are related to prematurity and organ immaturity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In some cases, patients died before CKD progression could be assessed. In addition, the kidney injuries in our cohort were often caused by nephrotoxic drugs, which tend to be reversible [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and neonatal kidneys may have a relatively high capacity for recovery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, standard methods for evaluating kidney function, such as eGFR and proteinuria, are difficult to apply in neonates, which may have led to underestimation of CKD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings suggest that neonatal AKD has a different outcome pattern compared to older patients, with mortality having a greater impact than CKD progression. However, the long-term effects on kidney function and kidney development in survivors require further study.\u003c/p\u003e\u003cp\u003eIn our cohort, neonates who developed AKD had lower gestational age and birth weight, lower Apgar scores, and were more likely to receive mechanical ventilation and vasoactive medications. These factors reflect greater illness severity and organ immaturity, which have been linked to kidney dysfunction in previous pediatric studies [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Nephrotoxic medications, especially aminoglycosides, were used more frequently in the AKD group, consistent with earlier reports highlighting the vulnerability of preterm kidneys to drug-related injury [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The most common causes of AKI in the AKD group were drug toxicity and cardiac disease, whereas non-AKD patients often had transient causes such as asphyxia or surgical procedures. Although most AKD cases started as AKI stage 1, the AKD group had more cases of stage 2, suggesting that even moderate AKI severity may be associated with persistent kidney dysfunction, as seen in older children [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our cohort, exposure to aminoglycosides and lower birth weight were identified as independent risk factors for AKD. Aminoglycosides are widely used in NICUs for the treatment of sepsis and other infections, but their association with kidney injury is well documented, particularly in preterm infants with immature renal function [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Lower birth weight likely reflects a combination of immaturity, vulnerability to hemodynamic instability, and limited renal reserve, which may increase susceptibility to sustained kidney damage. Previous studies in children and adults have also reported that drug-induced kidney injury can lead to prolonged or persistent dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our findings confirm that both immaturity and nephrotoxic exposure contribute to the development of AKD in neonates. This underscores the importance of strategies to avoid nephrotoxic medications in high-risk neonates and to closely monitor those with low birth weight, as emphasized in prior quality improvement efforts such as the Baby NINJA program [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCLD and IVH were common in neonates with AKD. These complications largely reflect the high proportion of extremely and very low birth weight infants in this cohort [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. While CLD and IVH are likely related to prematurity and overall illness severity, emerging evidence suggests potential bidirectional interactions between kidney injury and other organ dysfunctions, particularly lung injury [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Experimental and clinical studies have described pathways through which AKI can contribute to lung injury and vice versa, including inflammation, endothelial dysfunction, and fluid overload [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although the present study was not designed to establish causality between AKD and CLD or IVH, our findings underline the need for further research into how kidney dysfunction may interact with other organ systems in critically ill neonates.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, it was a single-center retrospective study, which may limit the generalizability of the findings. Second, some secondary outcomes, particularly proteinuria and blood pressure, had missing data, which may have led to underestimation of CKD and hypertension [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Notably, among the neonates who were tested, proteinuria was common, suggesting it is an important marker for kidney monitoring after AKD. The low testing rate likely reflects limited collaboration between neonatologists and pediatric nephrologists, highlighting the need for better multidisciplinary follow-up. Third, we defined nephrotoxic medication exposure based only on aminoglycosides, vancomycin, NSAIDs, acyclovir/valacyclovir, and renin-angiotensin system-inhibitor. While we could not assess all potential nephrotoxic agents, these five drug classes are widely recognized as the most common nephrotoxic medications in neonatal AKI studies and likely captured the majority of relevant exposures. Finally, current AKI definitions in neonates, particularly extremely low birth weight infants, may capture non-pathological creatinine changes, risking overdiagnosis. In contrast, AKD criteria may better identify neonates with clinically significant and persistent kidney dysfunction. Our findings support AKD as a useful framework for recognizing neonates at higher risk of adverse outcomes.\u003c/p\u003e\u003cp\u003eIn conclusion, neonatal AKD was common and was associated with increased risks of mortality and major adverse kidney events. Exposure to aminoglycosides and lower birth weight were identified as independent risk factors. Our findings suggest that AKD is a valuable concept for identifying neonates at higher risk of poor outcomes. Improved collaboration between neonatologists and pediatric nephrologists is essential to monitor and manage long-term kidney health in this vulnerable population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003cp\u003eThe authors have no conflicts of interest relevant to this article to disclose. An honorarium, grant, or other form of payment was not provided to any of the authors to produce the manuscript.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics Approval:\u003c/h2\u003e\u003cp\u003e This retrospective study was performed in line with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Health, Labour and Welfare, Japan. The protocol for the study received approval from the Ethics Committee of the NCCHD (Approval No.: 2024-074). Informed consent was deemed unnecessary according to these ethical guidelines. However, we ensured transparency by publicly disclosing the study information on the institutional website, allowing participants or their guardians to opt out if desired.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003cp\u003eKN prepared the first draft of the manuscript and was responsible for data collection supervision, data curation, formal analysis, investigation, and visualization. He also served as the primary investigator and supervised the project, including its administration. SO, TI, YM, and HA contributed to data collection and interpretation and participated in manuscript editing and review. HC performed data curation, formal analysis, investigation, and visualization. KF and TM revised the manuscript for important intellectual content. KK, TF, TI, and YI provided study supervision, critical manuscript revision, and contributed to funding acquisition. All authors were involved in the study\u0026rsquo;s conceptualization and design, approved the final manuscript, and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis research was funded by a grant from the National Center for Child Health and Development (grant number: 2024B-9).\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\u003cp\u003eThe authors used ChatGPT (OpenAI) to assist with English editing of the manuscript draft. All edits were reviewed and finalized by the authors. Final language polishing was conducted by a professional editing service. We would like to thank the medical editor from the Center for Postgraduate Education and Training, National Center for Child Health and Development for editing a draft of this manuscript.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e\u003cp\u003eDeidentified individual participant\u0026rsquo;s data will not be made available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChawla LS, Bellomo R, Bihorac A, Acute Disease Quality Initiative Workgroup 16 et al (2017) Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. 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Sci Adv 8:eabm5900. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1126/sciadv.abm5900\u003c/span\u003e\u003cspan address=\"10.1126/sciadv.abm5900\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRanieri VM, Suter PM, Tortorella C et al (1999) Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 282:54\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jama.282.1.54\u003c/span\u003e\u003cspan address=\"10.1001/jama.282.1.54\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHerrlich A (2022) Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury. FEBS Lett 596:620\u0026ndash;637. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/1873-3468.14262\u003c/span\u003e\u003cspan address=\"10.1002/1873-3468.14262\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable I. Overall patient characteristics and baseline comparison between the AKD and non-AKD groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"577\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003cp\u003e(n = 280)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003eAKD group\u003c/p\u003e\n \u003cp\u003e(n = 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003eNon-AKD group\u003c/p\u003e\n \u003cp\u003e(n = 195)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e151 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e51 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e100 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eGestational age (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e29 (26\u0026ndash;33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e25 (24\u0026ndash;29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e30 (27\u0026ndash;35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026lt; 28 weeks\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 28\u0026ndash;33 weeks\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026ge; 34 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e109 (39)\u003c/p\u003e\n \u003cp\u003e106 (37)\u003c/p\u003e\n \u003cp\u003e68 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e55 (65)\u003c/p\u003e\n \u003cp\u003e20 (24)\u003c/p\u003e\n \u003cp\u003e9 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e53 (27)\u003c/p\u003e\n \u003cp\u003e86 (44)\u003c/p\u003e\n \u003cp\u003e57 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eBirth weight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e1160 (716\u0026ndash;1978)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e767 (554\u0026ndash;1281)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e1282 (854\u0026ndash;2117)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026lt; 1000 g\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 1000\u0026ndash;1500 g\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026ge; 1500 g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e105 (37)\u003c/p\u003e\n \u003cp\u003e61 (22)\u003c/p\u003e\n \u003cp\u003e117 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e34 (40)\u003c/p\u003e\n \u003cp\u003e20 (24)\u003c/p\u003e\n \u003cp\u003e30 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e70 (36)\u003c/p\u003e\n \u003cp\u003e40 (20)\u003c/p\u003e\n \u003cp\u003e86 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eApgar score at 1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e4 (2\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e5 (3\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eApgar score at 5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e7 (5\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e6 (5\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e7 (5\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eAge at AKI onset (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e2 (2\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e2 (2\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e2 (2\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eVentilator\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e231 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e79 (96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e152 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eInotrope\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; 165 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e59 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e106 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eInfection\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e10 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e2 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e8 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eSepsis\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e9 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e4 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eCardiac surgery\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 2 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eNon-cardiac surgery*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;15 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e3 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e12 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eContrast agent\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 4 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e3 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eCardiac arrest\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 1 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eDiuretics\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e54 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e17 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e37 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eNephrotoxic medications\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; 207 (74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e73 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e134 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eAminoglycosides\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Vancomycin\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;NSAIDs\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Acyclovir/valacyclovir\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;RAS-inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp; 183 (65)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;5 (2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 83 (30)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;0 (0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e67 (80)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e29 (35)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e116 (59)\u003c/p\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003cp\u003e54 (28)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eUnderlying disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e217 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e68 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e149 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Cardiac\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Respiratory\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Kidney\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e101 (36)\u003c/p\u003e\n \u003cp\u003e12 (4)\u003c/p\u003e\n \u003cp\u003e6 (2)\u003c/p\u003e\n \u003cp\u003e100 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e36 (42)\u003c/p\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003cp\u003e31 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e65 (33)\u003c/p\u003e\n \u003cp\u003e10 (5)\u003c/p\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003cp\u003e70 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eCause of AKI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Drug-induced\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Cardiac disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Neonatal asphyxia\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Surgical procedures\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Prerenal causes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e101 (36)\u003c/p\u003e\n \u003cp\u003e57 (20)\u003c/p\u003e\n \u003cp\u003e24 (8)\u003c/p\u003e\n \u003cp\u003e13 (5)\u003c/p\u003e\n \u003cp\u003e5 (2)\u003c/p\u003e\n \u003cp\u003e83 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e40 (52)\u003c/p\u003e\n \u003cp\u003e20 (26)\u003c/p\u003e\n \u003cp\u003e5 (6)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e4 (5)\u003c/p\u003e\n \u003cp\u003e17 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e61 (36)\u003c/p\u003e\n \u003cp\u003e37 (22)\u003c/p\u003e\n \u003cp\u003e19 (11)\u003c/p\u003e\n \u003cp\u003e13 (8)\u003c/p\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003cp\u003e66 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003eStage at AKI onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.4783%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Stage 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Stage 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Stage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.3913%;\"\u003e\n \u003cp\u003e213 (77)\u003c/p\u003e\n \u003cp\u003e63 (23)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e58 (70)\u003c/p\u003e\n \u003cp\u003e25 (30)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.6522%;\"\u003e\n \u003cp\u003e155 (80)\u003c/p\u003e\n \u003cp\u003e38 (20)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8261%;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as n (%) or median (interquartile range).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAKI, acute kidney injury; AKD, acute kidney disease; NSAIDs, nonsteroidal anti-inflammatory drugs; RAS, renin-angiotensin system\u003c/p\u003e\n\u003cp\u003e* Data collected before AKI onset.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable II. Outcomes of neonates with and without AKD\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003cp\u003e(n = 280)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003eAKD group\u003c/p\u003e\n \u003cp\u003e(n = 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003eNon-AKD group\u003c/p\u003e\n \u003cp\u003e(n = 195)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eDeath within 90 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e10 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e7 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e3 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eCKD stage \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 19 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e9 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e10 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eDialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e2 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eMAKE90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 27 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e14 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e13 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eProteinuria\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp;47/102 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e20/36 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e27/66 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eHypertension\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp;1/252 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e0/77 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e1/175 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eCLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;158 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e64 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e94 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.866%;\"\u003e\n \u003cp\u003eIVH\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Grade 3\u0026ndash;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Grade 1\u0026ndash;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e64 (23)\u003c/p\u003e\n \u003cp\u003e18 (6)\u003c/p\u003e\n \u003cp\u003e46 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e32 (38)\u003c/p\u003e\n \u003cp\u003e8 (10)\u003c/p\u003e\n \u003cp\u003e24 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0459%;\"\u003e\n \u003cp\u003e32 (16)\u003c/p\u003e\n \u003cp\u003e10 (5)\u003c/p\u003e\n \u003cp\u003e22 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4039%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAKD\u003c/strong\u003e, acute kidney disease; \u003cstrong\u003eCKD\u003c/strong\u003e, chronic kidney disease; \u003cstrong\u003eCLD\u003c/strong\u003e, chronic lung disease; \u003cstrong\u003eIVH\u003c/strong\u003e, intraventricular hemorrhage; \u003cstrong\u003eMAKE90\u003c/strong\u003e, major adverse kidney events at 90 days\u003c/p\u003e\n\u003cp\u003e* Proteinuria was assessed in 102 patients who underwent urine testing.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u0026dagger; Hypertension was assessed in 252 patients with available blood pressure measurements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable III. Multivariable logistic regression analysis of AKD development\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"95%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eLower birth weight per 100 g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e2.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e1.11\u0026ndash;1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eApgar score at 5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.81\u0026ndash;1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eExposure to aminoglycosides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e2.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e1.07\u0026ndash;4.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eAKI \u0026ge; Stage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.74\u0026ndash;2.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAKI, acute kidney injury; CI, confidence interval; OR, odds ratio\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"neonate, acute kidney injury, NICU, children, nephrotoxic medications, chronic kidney disease","lastPublishedDoi":"10.21203/rs.3.rs-7037915/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7037915/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Acute kidney disease (AKD) is defined as kidney dysfunction lasting 7–90 days after an initiating event. Although widely recognized in adults and children, its significance in neonates is unclear. We aimed to investigate the risk factors and outcomes of neonatal AKD in a cohort of neonates with acute kidney injury (AKI).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We performed a retrospective cohort study at a tertiary NICU in Japan. Among 345 neonates with AKI between 2014 and 2024, 280 were included after excluding cases with congenital kidney disease, early death (\u0026lt; 7 days), or missing data. AKD was defined by KDIGO/ADQI criteria. We compared clinical features and outcomes between neonates with and without AKD and used multivariable logistic regression to identify predictors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf 280 neonates with AKI, 85 (30%) developed AKD. Compared to non-AKD neonates, those with AKD had higher 90-day mortality (8% vs. 2%, \u003cem\u003eP\u003c/em\u003e= 0.005) and MAKE90 (17% vs. 7%, \u003cem\u003eP\u003c/em\u003e= 0.014). Chronic lung disease (78% vs. 50%, \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001) and intraventricular hemorrhage (38% vs 16%, \u003cem\u003eP\u003c/em\u003e= 0.002) were also more common in the AKD group. In multivariable analysis, aminoglycoside exposure (OR = 2.04; 95% CI, 1.07–4.04; \u003cem\u003eP\u003c/em\u003e= 0.031) and lower birth weight (per 100 g) (OR = 2.73; 95% CI, 1.11–1.22; \u003cem\u003eP\u003c/em\u003e= 0.002) were independently associated with AKD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Neonatal AKD was common and associated with increased mortality and major adverse kidney events. Our findings support AKD as a useful concept for identifying high-risk neonates and highlight the need for long-term kidney monitoring in this vulnerable population.\u003c/p\u003e","manuscriptTitle":"Neonatal acute kidney disease in the NCCHD-neoAKI Cohort: risk factors and prognostic outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 11:51:37","doi":"10.21203/rs.3.rs-7037915/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-07-12T13:33:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-10T09:42:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-04T13:07:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2025-07-03T07:31:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d40ed52e-aa6b-43ea-80ec-1b57ad08b4d5","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:24:24+00:00","versionOfRecord":{"articleIdentity":"rs-7037915","link":"https://doi.org/10.1007/s00467-025-07011-w","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2025-10-22 16:16:07","publishedOnDateReadable":"October 22nd, 2025"},"versionCreatedAt":"2025-07-14 11:51:37","video":"","vorDoi":"10.1007/s00467-025-07011-w","vorDoiUrl":"https://doi.org/10.1007/s00467-025-07011-w","workflowStages":[]},"version":"v1","identity":"rs-7037915","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7037915","identity":"rs-7037915","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}